1. Field of the Invention:
The present invention relates to novel and useful derivatives of non-steroidal anti-inflammatory drugs containing a carboxylic acid function. In particular, the present invention relates to novel forms of these non-steroidal anti-inflammatory drugs characterized as being (1) more readily bioavailable; (2) less irritating to topical and gastric mucosal membranes; and (3) more permeable through topical membranes such as the ophthalmic membrane, skin, etc., when administered orally or topically to warm-blooded animals than are the non-steroidal anti-inflammatory drugs from which they are derived.
For the purposes of this specification, the term "prodrug" denotes a derivative of a known and proven prior art non-steroidal anti-inflammatory compound (e.g., indomethacin, aspirin, naproxen, etc.), which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form at its target site or sites of activity. The enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention occurs in such a manner such that the proven drug form (the conventional non-steroidal anti-inflammatory agent) is released while the remaining "cleaved" moiety remains nontoxic and is metabolized in such a manner that nontoxic, metabolic products are produced.
2. Description of the Prior Art
Usually, the un-ionized form of a drug is absorbed more efficiently than its ionic species. In the case of non-steroidal anti-inflammatory drugs containing the carboxylic acid functional group such as indomethacin, aspirin, naproxen and the like, the carboxylic acid is significantly ionized at physiological pH. The result is that such non-steroidal anti-inflammatory drugs are poorly absorbed through lipid-water membrane barriers and are irritating. Thus, an object of the present invention is to provide a class of derivatives of non-steroidal anti-inflammatory drugs which would not be significantly ionized at physiological pH and which are reasonably stable but which hydrolyze readily in vivo.
The present derivatives of non-steroidal anti-inflammatory drugs are basic compounds, each compound being the acylate of a hydroxylamine; however, by virtue of the oxygen-nitrogen bond, the pK.sub.a of the amine is lowered to well below 7.0 so that, at physiological pHs, the derivative is in its unionized form. In addition, the present derivatives of non-steroidal anti-inflammatory drugs are reasonably stable, reacting only slowly with highly nucleophilic amines in the absence of acid catalyst [B. O. Handford, T. H. Jones, G. T. Young and T. F. N. Johnson, J. Chem. Soc., 6814 (1965)] while it can be expected that in vivo such derivatives will be rapidly cleaved by esterases.
The result of the hydrolysis of the novel prodrug derivatives of the present invention yields the known anti-inflammatory drug and one molecule of an N-hydroxydialkylamine or similar N-hydroxydi(substituted)amine. N-oxidation of dialkylamines is one of the metabolic pathways for elimination of dialkylamines and there appears to be an equilibrium between the dialkylamine and its N-oxidized form which is reduced pyridine nucleotide-dependent. [F. F. Kadlubar, E. M. McKee, D. M. Ziegler, Arch. Biochem. Biophys., 156, 46 (1973)] Thus, the N-hydroxydialkylamine is comparable in toxicity to the dialkylamine from which it is derived.
The derivatives of the non-steroidal anti-inflammatory drugs of the present invention therefore provide more easily absorbed and less irritating forms of the un-ionized state of the drug. In addition, the hydrolysis of the derivatives of the present invention yield only the parent non-steroidal anti-inflammatory drug and a nontoxic N-hydroxyamine which is readily eliminated.